Main Objective (EudraCT):To evaluate the safety and tolerability of RO7198457 when administered as a single agent (Phase [Ph] Ia) or in combination with atezolizumab (Ph Ib), with or without prophylactic treatment with corticosteroids, including…
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Source
Brief title
Condition
- Metastases
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Incidence and nature of DLTs
2. Incidence, nature, and severity of adverse events graded according to
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI
CTCAE) v5.0
3. Incidence, nature, and severity of immune-mediated adverse event graded
according to NCI CTCAE v5.0
4. Change from baseline in targeted vital signs
5. Change from baseline in targeted clinical laboratory test results, including
ECGs
6. Number of cycles received and dose intensity.
Secondary outcome
1. Objective response (OR) defined as a complete response or partial response
as per RECIST v1.1
2. Duration of response (DoR) the time from the first occurrence of a
documented objective response to the time of the first documented disease
progression (DP)or death from any cause, whichever occurs first, per RECIST
v1.1 as determined by the investigator
3. OR and DoR as determined using immune-modified RECIST
4. Progression free survival defined as the time from the first study treatment
(D1) to the first occurrence of progression or death from any cause, whichever
occurs first, per RECIST v1.1 as determined by the investigator
5. Overall survival defined as the time from first study treatment to death
from any cause
6. Incidence of ADA to atezolizumab (Ph Ib) and the potential correlation with
PK, pharmacodynamics, safety, and preliminary efficacy parameters.
Background summary
The role of the immune system in controlling the growth of cancer has been
demonstrated by the efficacy of cancer immunotherapy (CIT) in a variety of
tumor types leading to survival benefits in clinical trials. While this
represents a major advance in the fight against cancer, only a minority of
patients respond to immune checkpoint inhibition. Understanding mechanisms of
resistance and developing novel combinations that extend the benefit to more
patients is a key next step to further improving outcomes. (§1.1)
This study aims to evaluate the safety, pharmacokinetics, immune response, and
preliminary anti tumor activity of RO7198457 in combination with atezolizumab
in patients with locally advanced or metastatic tumors as a rational strategy
to potentiate anti tumor immune responses and to enhance the benefit associated
with immune checkpoint blockade.
Background of RO7198457
RO7198457 is a personalized cancer vaccine (PCV) that is based on the
immunotherapeutic targeting of the unique mutations in a given patient*s
tumor. Multiple key technologies have been combined to generate a controlled
process that covers all steps from identification of mutations in individual
clinical tumor specimens to the supply of an individually tailored RNA vaccine
for use in a specific patient.
The manufacture of RO7198457 is a multi step process, whereby somatic mutations
in the patient*s tumor are identified by next generation sequencing (NGS) and
immunogenic neoantigen epitopes (or *neoepitopes*) are predicted. The RNA
cancer vaccine targeting the selected neoepitopes is manufactured on a per
patient basis. The investigational medicinal product (IMP) generated in this
process is an RNA based cancer vaccine consisting of up to two messenger RNA
molecules, each encoding up to 10 neoepitopes (for a total of up to 20
neoepitopes), which are specific to the patient*s tumor. A lipoplex
nanoparticle formulation for the RNA (RNA Lipoplex) is used to enable
intravenous (IV) delivery of RO7198457. There are three critical vaccine
components that determine the type and strength of the immune response: 1) the
antigens, 2) the delivery platform that brings antigens to DCs for presentation
to T cells, and 3) the adjuvant that provides the immuno-stimulatory signal to
DCs that shapes the outcome of the immune response. These three critical
components are all incorporated in RO7198457.
Expressed non synonymous mutations are identified by whole exome sequencing of
tumor DNA and PBMC DNA (as a source of healthy tissue from the patient) as well
as tumor RNA sequencing (to assess expression).
Vaccinating against multiple neoepitopes is expected to increase the breadth
and magnitude of the overall immune response to the PCV and may help to
mitigate the risk of immune escape, which can occur when tumors are exposed to
the selective pressure of an effective immune response.
As shown in three independent tumor models, the RNA vaccine platform conferred
strong anti tumor immunity. A considerable fraction of non synonymous cancer
mutations were immunogenic, eliciting both CD4 and CD8 T cell responses. Most
importantly, these models demonstrated that vaccination with RNA vaccines
induced potent tumor control and complete rejection of aggressively growing
tumors in mice. In addition, they demonstrated that CD4 T cell response alone
induced by vaccination was sufficient to control tumor growth through multiple
mechanisms such as reshaping the tumor microenvironment and stimulating CD8 T
cell responses. In addition, in the HPV16 E7 expressing TC1 mouse model, the
combination of the RNA vaccine targeting E7 with anti PD*L1 resulted in a
longer survival benefit than monotherapies (see Section 1.4).
The combination of RO7198457 and anti PD*L1 represents an attractive strategy
for CIT and is expected to enhance the magnitude and quality of the tumor
specific T cell responses, which may result in increased anti tumor activity
that might be observed with RO7198457 or atezolizumab as a single agent.
RO7198457 is being investigated as a potential therapy against tumors in
humans.
Background on Atezolizumab
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody (mAb)
that targets PD L1 and inhibits the interaction between PD L1 and its
receptors, PD 1 and B7 1 (also known as CD80), both of which function as
inhibitory receptors expressed on T cells. Therapeutic blockade of PD L1
binding by atezolizumab has been shown to enhance the magnitude and quality of
tumor specific T cell responses, resulting in improved anti-tumor activity.
Atezolizumab has minimal binding to Fc receptors, thus eliminating detectable
Fc effector function and associated antibody mediated clearance of activated
effector T cells.
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer
patients and is being investigated as a potential therapy in a wide variety of
malignancies. Atezolizumab is being studied as a single agent in the advanced
cancer and adjuvant therapy settings, as well as in combination with
chemotherapy, targeted therapy, and CIT.
Atezolizumab is approved in the United States for the treatment of locally
advanced or metastatic urothelial carcinoma (mUC) and for the treatment of
metastatic NSCLC.
Study objective
Main Objective (EudraCT):
To evaluate the safety and tolerability of RO7198457 when administered as a
single agent (Phase [Ph] Ia) or in combination with atezolizumab (Ph Ib), with
or without prophylactic treatment with corticosteroids, including estimation of
the maximum tolerated dose and the recommended Ph II dose and characterization
of dose-limiting toxicities (DLTs).
Study design
Description of Study
This is a Phase Ia/Ib, open label, multicenter, global, dose escalation study
designed to evaluate the safety, tolerability, immune response, and
pharmacokinetics of RO7198457 as a single agent and in combination with
atezolizumab. Approximately 307-770 patients will be enrolled into this study
at approximately 20-40 sites globally.
Phase Ib portion:
In this combination part of the study, eligible patients are those with locally
advanced, recurrent, or metastatic incurable tumors for whom standard therapy
does not exist, has proven to be ineffective or intolerable, or is considered
inappropriate, or for whom a clinical trial of an investigational agent is a
recognized standard of care, or for whom a clinical trial of an investigational
agent in combination with an anti programmed death ligand 1 (anti PD-L1)
antibody is considered an acceptable treatment option.
This Phase Ib portion will be organized into five groups: flat-dose escalation,
flat-dose escalation with prophylactic corticosteroid treatment, step-up dose
escalation, dose exploration, and dose expansion group.
Flat-dose escalation group (with or without prophylactic corticosteroid
treatment): Approximately 3-6 patients, in each group, were to be evaluated at
escalating dose levels starting with a dose of 25 ug with escalations to 38,
50, 75 and 100 ug RO7198457 in combination with 1200 mg atezolizumab to
determine the MTD for RO7198457 in combination with atezolizumab. The MTD and
MAD for RO7198457, as a signle agent or in combination with atezolizumab, may
be different in dose-escalation cohorts with prophylactic corticosteroid
treamtent. Other doses of RO7198457 may be studied if they do not exceed the
MTD.
Combination dosing at higher dose levels will only begin after the dose
limiting toxicities (DLT) evaluations of the respective dose levels in the
single agent RO7198457 (Phase Ia) portion, as well as the lower dose level in
the combination (Phase Ib) portion, have been completed and the relevant safety
data thoroughly reviewed with the investigators. If the combination safety is
deemed appropriate, dose escalation in the Phase Ib portion will then continue
at a dose level no higher than the tested RO7198457 dose level, using the same
dose escalation scheme and comprehensive safety monitoring plan as in the Phase
Ia portion. Additional patients may be enrolled in doses that have cleared DLT
assessment. In the group with prophylactic corticosteroid treatments, the
corticosteroid will be administered approximately 1 hour after RO7198457
infusion.
Step-up dose-escalation group: Approximately 3-9 patients will be enrolled into
each step-up target-dose cohort to receive increasing doses of RO7198457 in
combination with 1200 mg atezolizumab. The starting dose at Cycle 1, Day 1 (25
*g or 50 *g RO7198457) must be cleared in Phase Ib flat dose escalation prior
to initiating step-up dosing. However, step-up doses beyond the starting dose
in each step-up dose cohort (i.e., Cycle 1, Day 8 and beyond) may exceed dose
levels cleared in the Phase Ib flat dose escalation. The Sponsor, in
consultation with the study investigators, may decide to test intermediate or
lower doses depending on the safety and tolerability of RO7198457.
Dose exploration group: In this group, approximately 20-40 patients with CIT
treated non small cell lung cancer (NSCLC) may be enrolled between the two
cohorts to receive 15ug or 25 ug RO7198457 in combination with atezolizumab.
These dose levels will be at or below those at which MTD has not been exceeded,
per the safety and toxicity data from the Phase Ib flat dose-escalation portion
of the study. Up to two additional dose-exploration cohorts of 20-40 patients
with NSCLC who are CIT-experienced or 20-40 patients with melanoma who are
CIT-experienced may be added at or below the MTD/MAD using flat dosing (with or
without prophylactic corticosteroid treatment) or step-up dosing, depending
upon emerging data from the Phase Ib portion of the study and/or other external
supportive data. The administration of RO7198457 prior to (rather than
following) infusion of atezolizumab will be implemented in certain cohorts in
the Phase Ib dose-exploration group in order to evaluate impact on acute
tolerability. The decision to add additional dose exploration cohorts will be
reviewed by the Sponsor in consultation with the study investigators.
Dose expansion group: In this group, 20-40 patients will be enrolled into each
indication-specific cohort and treated at or below the MTD/MAD of RO7198457 in
combination with atezolizumab (Phase Ib). In the Phase Ib indication-specific
expansion cohorts, multiple doses of RO7198457 at or below the MTD/MAD of flat
dosing (with or without prophylactic corticosteroid treatment) or step-up
dosing may be explored based upon the accumulated safety, immune monitoring,
and efficacy data in the dose-escalation and dose-exploration components.
All Phase Ib groups: The combination of RO7198457 and atezolizumab will be
administered by IV infusion with RO7198457 being administered 30 minutes after
atezolizumab. Patients will receive atezolizumab on Cycle 1 Day 1 and on Day 1
of each subsequent cycle of treatment. RO7198457 will begin in Cycle 1 and be
administered on Cycle 1 Days 1, 8, and 15; Cycle 2 Days 1, 8, and 15; Cycle 3
Days 1 and 15; and Cycle 7 Day 1 and then as continued treatment every 8 cycles
starting at Cycle 13. Each cycle comprises 21 days. This schedule may be
utilized in the flat dose-escalation, step-up dose-escalation, dose-exploration
and/or dose-expansion. In the biopsy cohort, a staggered dosing paradigm (i.e.,
1 cycle of atezolizumab run in) will be employed in order to clearly assess the
effect of each component of the combination. Atezolizumab will begin on Cycle
1, Day 1 and RO7198457 will be administered Cycle 2 Days 1, 8, and 15; Cycle 3
Days 1, 8, and 15; Cycle 4 Days 1 and 15; and Cycle 7 Day 1 and then as
continued treatment every 8 cycles starting at Cycle 13. In addition, cancer
immunotherapy (CIT-)-naïve patients in the Phase Ib portion of the study may be
able to receive up to 1 cycle of atezolizumab prior to starting the combination
with RO7198457 in urgent situations (e.g., vaccine delivery is delayed and
patient is ready to receive a dose) following conversation with the Medical
Monitor.
Patients in the dose-exploration or dose-expansion cohorts may also follow the
following schedule: Patients will receive atezolizumab on Cycle 1, Day 1 and on
Day 1 of each subsequent cycle of treatment. RO7198457 will be administered on
Cycle 1, Days 1 and 8; Day 1 of each subsequent cycle of treatment until Cycle
7; and then as continued treatment every 8 cycles starting at Cycle 13.
NSCLC sub-study:
the Dutch sites have declined participation, hence all reference to this
sub-study removed.
Length of Study
The total length of the study, from screening of the first patient to the end
of the study, is expected to be approximately 36 months.
Intervention
Investigational Medicinal Products
Test Product (Investigational Drug)
RO7198457 is an investigational medicinal product (IMP) within this study.
RO7198457 will be administered after the atezolizumab infusion and subsequent
observation period, as described below.
Atezolizumab is an IMP within the Phase Ib portion of the study. Atezolizumab
1200 mg IV every 3 weeks (Q3W) will be administered in combination with
RO7198457 in the Phase Ib portion of this study. This dose is fixed and not
dependent on body weight. Atezolizumab will be administered prior to the
RO7198457 infusion.
For specific cohorts in dose-exploration agreed upon by the Sponsor in
discussion with investigators, the order of administration will be reversed
such that RO7198457 is administered first and followed by atezolizumab 30
minutes later.
Study burden and risks
The side effects of PCV in humans are unknown as this is a first-in-men study.
The subjects will be monitored closely by the study/nursing staff.
The risk for immune related adverse events may be increased when immune
enhancing agents are given in combination with atezolizumab. Systemic immune
activation, characterized by an excessive immune response, is a potential risk
associated with atezolizumab when used in combination with another
immunomodulating compound.
In trials investigating the combinations of atezolizumab with chemotherapy,
bevacizumab, bevacizumab plus chemotherapies, vemurafenib (BRAF inhibitor), or
cobimetinib (mitogen activated protein kinase [MEK] inhibitor), the incidence
of adverse events in the treatment arms with combined use was consistent with
the known safety profiles of the individual study drugs.
Emil-Barell-Strasse 1
Grenzach-Whylen 79639
DE
Emil-Barell-Strasse 1
Grenzach-Whylen 79639
DE
Listed location countries
Age
Inclusion criteria
• Age >=18
• Eastern Cooperative Oncology Group performance (ECOG) status of 0 or 1
• Life expectancy >= 12 weeks
• Adequate hematologic and end-organ function
• Measured or calculated creatinine clearance >= 50 mL/min
• Agrees to use protocol defined methods of contraception,
Cancer-Specific Inclusion Criteria
• Patients with histologic documentation of locally advanced, recurrent, or
metastatic incurable malignancy that has progressed after at least one
available standard therapy; or for whom standard therapy has proven to be
ineffective or intolerable, or is considered inappropriate; or for whom a
clinical trial of an investigational agent is a recognized standard of care
• Patients with measurable disease per Response Evaluation Criteria for Solid
Tumors v1.1, Additional Inclusion Criteria for Phase 1b Patients Who Backfill
Cleared Cohorts
• Backfill cohort enrollment may be limited to patients whose tumors have
programmed death-ligand 1 (PD-L1) and/or different levels of CD8 expression
• Backfill enrollment in Phase 1b may be managed such that approximately half
of the patients in each backfill cohort will not have been treated with prior
immune checkpoint inhibitors, except for those patients with tumor indications
where CIT is approved as therapy by local regulatory authorities.
Additional Inclusion Criteria for Patients in Each Phase 1b Indication-Specific
Exploration/Expansion Cohort
• Non-small cell lung cancer (NSCLC) Cohorts (CIT-Naïve): Patients with
histologically confirmed incurable, advanced NSCLC not previously treated with
anti-PD*L1/PD-1 and/or anti- cytotoxic T-lymphocyte-associated protein 4
(CTLA*4), for whom a clinical trial of an investigational agent in combination
with an anti-PD*L1 antibody is considered an acceptable treatment option
• NSCLC Cohort (CIT-Treated): Patients with histologically confirmed incurable,
advanced NSCLC previously treated with antiPD*L1/ PD-1 with or without anti
CTLA-4
• Triple Negative Breast Cancer (TNBC) Cohort (CIT-Naïve): Patients with
histologically confirmed incurable, advanced estrogen-receptor-negative,
progesterone receptor-negative, and human epidermal growth factor receptor 2
(HER-2)-negative adenocarcinoma of the breast (triplenegative) not previously
treated with anti-PD-L1/PD-1 and/or anti CTLA-4
• Colorectal cancer (CRC) Cohort (CIT-Naïve): Patients with histologically
confirmed incurable, advanced adenocarcinoma of the colon or rectum not
previously treated with anti-PD-L1/PD-1 and/or anti CTLA-4
• Head and Neck Squamous Cell Carcinoma (HNSCC) Cohort (CIT-Naïve): Patients
with histologically confirmed inoperable, locally advanced or metastatic,
recurrent, or persistent HNSCC not amenable to curative therapy not previously
treated with anti-PD-L1/PD-1 and/or anti CTLA-4
• Urothelial Carcinoma (UC) Cohort (CIT-Naïve): Patients with histologically
confirmed incurable, advanced transitional cell carcinoma of the urothelium,
including renal pelvis, ureters, urinary bladder, and urethra, not previously
treated with anti-PD*L1/PD-1 and/or anti-CTLA*4, for whom a clinical trial of
an investigational agent in combination with an anti-PD*L1 antibody is
considered an acceptable treatment option, if CIT (including anti-PD*L1/PD-1
agents) is approved as treatment for UC
• UC Cohort (CIT-Treated): Patients with histologically confirmed incurable
advanced transitional cell carcinoma of the urothelium previously treated with
anti-PD*L1/PD-1 with or without CTLA-4 including anti-PD-L1/PD-1
• Renal Cell Carcinoma (RCC) Cohort (CIT-Naïve): Patients with histologically
confirmed incurable, advanced RCC with component of clear cell histology and/or
component of sarcomatoid histology not previously treated with anti-PDpL1/PD-1
and/or anti CTLA-4
• Melanoma Cohort (CIT-Naïve in metastatic setting): Patients with
histologically confirmed incurable, advanced melanoma not previously treated
with anti-PD-L1/PD-1 with or without anti CTLA-4 in the metastatic setting
• Melanoma Cohort (CIT-treated): Patients with histologically confirmed
incurable, advanced melanoma previously treated with anti-PD-L1/PD-1 with or
without anti CTLA-4.
Additional Inclusion Criteria for Patients in the Serial-Biopsy Expansion
Cohort of Phase Ib
• Patients must have one of the following tumor types: NSCLC, SCLC, UC, RCC,
TNBC, HNSCC, melanoma (excluding ocular), cervical, Merkel-cell carcinoma, SCC
of the skin, hepatocellular carcinoma (non -viral), or microsatellite
stability-high (MSH) tumors
• Patients must not have received prior treatment with CIT
• Patients must have accessible lesion(s) that permit a total of two to three
biopsies or one biopsy.
Exclusion criteria
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study
entry.
• Pregnancy, breastfeeding, or intending to become pregnant during the study or
within 90 daysafter the last dose of RO7198457 or 5 months after the last dose
of atezolizumab, whichever occurs later
• Known clinically significant liver disease, including active viral,
alcoholic, or other hepatitis, cirrhosis, and inherited liver disease or
current alcohol abuse
• Major surgical procedure within 28 days prior to Cycle (C) 1, Day (D) 1, or
anticipation of need for a major surgical procedure during the course of the
study
• Any other diseases, metabolic dysfunction, physical examination finding,
and/or clinical laboratory finding giving reasonable suspicion of a disease or
condition that contraindicates the use of an investigational drug or that may
affect the interpretation of the results or may render the patient at high risk
from treatment complications
• Previous splenectomy
• Known primary immunodeficiencies, either cellular or combined T- and B-cell
immunodeficiencies
• Any medical condition or abnormality in clinical laboratory tests that, in
the investigator's judgment, precludes the patient's safe participation in and
completion of the study,
Cancer-Specific Exclusion Criteria
• Any anti-cancer therapy, whether investigational or approved, including
chemotherapy, hormonal therapy, and/or radiotherapy, within 3 weeks prior to
initiation of study treatment
• Eligibility based on prior treatment with CIT and depends on the mechanistic
class of the drug and the cohort for which the patient is being considered
• Any history of an immune-mediated Grade 3 and 4 adverse event attributed to
prior CIT that resulted in permanent discontinuation of the prior
immunotherapeutic agent and/or occurred <=6 months prior to C1D1
• Adverse events from prior anti-cancer therapy that have not resolved to Grade
<= 1 except for alopecia, vitiligo, or endocrinopathy managed with replacement
therapy
• All immune-related adverse events related to prior CIT must have resolved
completely to baseline
• Primary central nervous system (CNS) malignancy, untreated CNS metastases, or
active CNS metastases, leptomeningeal disease
• Leptomeningeal disease
• Uncontrolled tumor-related pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring
recurrent drainage procedures and hypercalcemia
• Malignancies other than disease under study within 5 years prior to C1D1,
with the exception of those with a negligible risk of metastasis or death
• Patient has spinal cord compression not definitively treated with surgery
and/or radiation or previously diagnosed and treated spinal cord compression
without evidence that disease has been clinically stable for >=2 weeks prior to
screening, Treatment-Specific Exclusion Criteria
• History of autoimmune disease
• Treatment with monoamine oxidase inhibitors (MAOIs) within 3 weeks
prior to Cycle 1, Day 1
• Treatment with systemic immunosuppressive medications within 2 weeks prior to
C1D1
• History of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia,
or evidence of active pneumonitis on screening chest computed tomography scan
• Positive test for HIV infection
• Active hepatitis B and C
• Known Active or Latent tuberculosis infection
• Severe infections within 4 weeks prior to C1D1
• Recent infections not meeting the criteria for severe infections
• Prior allogeneic bone marrow transplantation or prior solid organ
transplantation
• Administration of a live, attenuated vaccine within 4 weeks before C1D1 or
anticipation that such a live attenuated vaccine will be required during the
study
• Known hypersensitivity to the active substance or to any of the excipients in
the vaccine
• Phase Ib and crossover, only:
* History of severe allergic, anaphylactic, or other hypersensitivity reactions
to chimeric or humanized antibodies or fusion proteins
* Known hypersensitivity to Chinese Hamster Ovary -cell products
* Allergy or hypersensitivity to components of the atezolizumab formulation.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-001475-23-NL |
| ClinicalTrials.gov | NCT03289962 |
| CCMO | NL61391.000.17 |